JPH04103525A - Production of sustainable pharmaceutical preparation for poorly water-soluble medicine - Google Patents

Abstract

PURPOSE:To obtain the title pharmaceutical preparation using a composition formed by dissolving or suspending a poorly water-soluble medicine in a solvent and spraying the resultant fluid on a carrier to effect adsorption while controlling the diameter of the droplets of said fluid to be sprayed to improve the solubility of said medicine. CONSTITUTION:A poorly water-soluble medicine such as nifedipine, isosorbide nitrate or theophylline is dissolved or suspended in a solvent such as an alcohol, water, dichloromethane and/or acetone (each containing appropriately a surfactant), and the resulting fluid is sprayed on a carrier to effect adsorption while controlling the diameter of the droplets of said fluid to improve the solubility of said medicine, thus obtaining the objective pharmaceutical preparation capable of sustainedly releasing said medicine, leading to manifesting stabilized efficacy thereof. When said medicine is nifedipine, it is preferable that the droplet's diameter be <=150mum, the medicinal content in the composition be <=50wt.% (in the presence of a surfactant) or <=20wt.% (in the absence of a surfactant), and the medicinal content in the spraying fluid be <=1.7wt.% (in the case of solution) or <=20wt.% (in the case of suspension).

Description

[Detailed description of the invention] (Industrial application field) The present invention relates to a method for producing a long-lasting formulation of a poorly water-soluble drug.

Examples of poorly water-soluble drugs targeted by the present invention include nifedipine, insorbide nitrate, theophylline, pindolol, dihydroergotoxine mesylate, and molsidomine. When the preparation is administered, the drug is released slowly, improving its bioavailability and stably exhibiting drug efficacy.

Although the present invention can be practiced with various poorly water-soluble drugs as described above, in this specification, "nifedipine" will be used as a representative example.

(Prior art, its problems, problems to be solved by the invention, and objects of the invention) Nifedipine is a yellow crystalline powder, and its solubility in water is about 12 μg/ml, so the crystalline powder can be orally administered as it is. However, it is said that the bioavailability rate is low at about 20% [Isao Sugimoto, “Infachem J VOl, 2
．． No. L page 17 (1981)].

Documents disclosing methods for producing solid preparations that exhibit stable drug efficacy by improving the solubility of nifedipine, which is sparingly soluble in water, and releasing it continuously, especially patent-related documents such as Japanese Patent Publication No. 59-14446 No., Equity Hei 1-22245
No., JP-A-Sho [io-255719, JP-A-61-8]
No., Japanese Unexamined Patent Publication No. Sho Gl-148114, etc.

Among these known technical documents, the method disclosed in Japanese Patent Publication No. 59+444fi has a specific surface area of 0.5-6 m2/
The aim is to rapidly increase the blood (plasma) concentration of the drug and maintain the high blood concentration for a long period of time by using H. nifedipine crystals and making an oral formulation using a conventional method. The problem is that the nifedipine crystals that can be used are limited.

The method disclosed in Jibu No. 1-22245 uses nifedipine fine powder with an average particle size of 5 μm or less, and coats one side with a poorly water-soluble substance and an enteric polymer to form a slow-release part. It is attempted to bring about a slow and sustained release of nifedipine by incorporating an uncoated fast-release part into the drug, but there is a problem in that the manufacturing process is complicated. Also, JP-A-80-2557
The method disclosed in No. 19 involves adding and mixing an enteric coating agent and a plasticizer to a co-pulverized fine powder composition obtained from a salt such as magnesium silicate or magnesium carbonate, casein, and nifedipine, and then co-pulverizing the composition. Although dry granulation is subsequently performed to form a solid preparation with excellent absorbency and sustainability, there is a problem in that the manufacturing process is complicated. On the other hand, the method disclosed in JP-A No. 61-8 uses a fast-dissolving granule prepared by adding a surfactant to nifedipine, and a portion of the granule is collected and pulverized. A sustained release granule prepared by adding a molecular fixing agent is mixed with the core layer and an enteric coating is applied to form a core layer. However, there is a problem in that the manufacturing process is complicated. In addition, Tokukai Sho fil
The method disclosed in Publication No. 148114 consists of fast-acting spherical granules consisting of a spherical core agent and fine powder of nifedipine attached to the surface thereof, and the fast-acting spherical granules being treated with an enteric substance and a poorly soluble substance. However, there is a problem in that the manufacturing process is complicated, and the problem to be solved by the present invention or the purpose of the invention is to use coated delayed-release spherical granules. It is not limited by the crystal grain size or specific surface area of the drug raw material (hereinafter sometimes referred to as "drug substance"), has a simple processing process, and is suitable for industrial production. The object of the present invention is to provide a method for producing a long-lasting drug.

(Means and effects for solving the problem and achieving the object) According to the present invention, the above problem is solved by dissolving or suspending a poorly water-soluble drug in a solvent, and then controlling the droplet size of the spray liquid to spray it onto a carrier. The above object is solved and achieved by using a composition obtained by spray adsorption.

When carrying out the present invention, poorly water-soluble drugs include nifedipine, isosorbide nitrate, theophylline, pindolol, dihydroergotoxine mesylate, molsidomine, and the like. Solvents for dissolving or suspending such poorly water-soluble drugs include ethanol, methanol,
Mention may be made of alcohols such as imbropanol, water, dichloromethane, acetone or mixtures thereof;
A surfactant can be added if necessary.

Examples of the surfactant in this case include polysorbate 80 and sodium lauryl sulfate.

The resulting poorly water-soluble drug solution or suspension is sprayed onto a carrier, which is a non-toxic carrier for pharmaceutical preparations, such as lactose, low-substituted hydroxypropylcellulose, crystalline cellulose, carboxymethylcellulose, or carboxylic acid. Examples include methyl cellulose calcium, pregelatinized starch, corn starch, and mixtures thereof.

When the poorly water-soluble drug is nifedipine, the concentration of nifedipine in the spray solution is set to 1.1% or less as a solution, or 20% or less as a suspension, and the droplet diameter of the spray solution is set to 150% or less.
μm or less, and the nifedipine content in the composition is
Setting the dissolution rate to 50% or less when a surfactant is present, and setting the dissolution rate to 20% or less when a surfactant is not present will ensure an appropriate dissolution rate, thereby providing a sustained action. Preferable from this point of view. In this case, the above droplet diameter is determined by the experimental formula such as extraction [[Proceedings of the Japan Society of Mechanical Engineers J Vol. 4]
゜page 128 (1938)], and as a guideline for an appropriate dissolution rate, the second method (paddle method, 1.
6 when the dissolution test was carried out using 0100rp.
This is a case where the elution rate after 0 minutes (Dai1) is within the range of 50±205f.

A composition obtained by spraying a solution or suspension of a poorly water-soluble drug onto a carrier can be dried and used as a powder, or it can be further formulated by a conventional method to form tablets, film tablets, sugar-coated tablets, capsules, and granules. It can be made into tablets, pre-split tablets, double-layered tablets, etc.

The reasons why poorly water-soluble drugs can be made into long-lasting formulations by the method of the present invention are ``partial amorphization due to dissolution of drug crystals'' and ``fineness of crystals due to penetration of solvent into the crystal wall interface.'' ”
It is presumed that this is because ``dispersion of aggregated crystals'' and the like occur, and these act synergistically.

(Examples etc.) Next, the present invention will be explained in more detail and concretely using Examples etc. which also serve as test examples. In the Examples below, nifedipine is exclusively used as the poorly water-soluble drug, but it should be noted that the method of the present invention can be applied to other poorly water-soluble drugs as well.

Orie 1 (powder) A 1.5% ethanol solution of nifedipine (technical substance) was sprayed and adsorbed onto lactose as a carrier using a fluidized bed granulation dryer to form a composition and powder. The active substance used has a specific surface area of 0.24 m2/g, and during spraying, the droplet diameter is set to various sizes by adjusting the conditions, and the amount ratio of lactose, which is a carrier, is set to various sizes. Samples were obtained in which the drug substance concentration in the resulting composition was varied, and the dissolution rate [Dai
That is, the second method (paddle method, dissolution rate after 60 minutes when the dissolution test is carried out at 10,100 rp) of the dissolution test methods prescribed in the Japanese Pharmacopoeia was investigated.

The results are shown in Table 1 below, and the droplet diameter was 15
The concentration of the drug substance in the composition is set to 0μm or less and sprayed.
It has been found that when the dissolution rate is below 0''A, the dissolution rate can be achieved within the range of 5o±20%, which is a guideline for improving solubility and determining duration of action.

In the table, (2): Weigh each sample composition so that it contains IOB of the drug substance, set the test liquid volume to 9001, and use the second method (paddle method) of the dissolution test methods specified in the Japanese Pharmacopoeia. N 10100r
Dissolution rate after 60 minutes when dissolution test was conducted using p.

Various sample compositions were prepared in the same manner as in Example 1, except that 1.0% 11 of porin rubey (.80) as a surfactant was added to a 1.5% ethanol solution of the drug substance (powder). (powder) was manufactured.

Regarding each of these sample compositions, a dissolution test was conducted in the same manner as in Example 1, and the dissolution rate (Dag) was determined after 60 minutes.
) was investigated. The results are shown in Table 2 below,
When the droplet diameter is set to 150 μm or less and the concentration of the drug substance in the composition is 50″A or less, the range of 50 ± 20% is the guideline for improving solubility and determining the duration of action. In other words, in the case of Example 1 in which no surfactant was added when preparing the drug composition, it was necessary to set the concentration of the drug substance in the composition to 20% or less. However, it has been found that by incorporating a surfactant, the desired effects of improved solubility and sustained drug efficacy can be achieved even if the drug substance concentration in the composition is set as high as about 50%. .

In the table, (1): Concentration of drug substance in sample (composition), (2): See Example ■.

! Jul (powder) An ethanol suspension of the raw material was sprayed and adsorbed onto lactose as a carrier using a fluidized bed granulation dryer to form a composition and a powder. However, in the case of this example, drug substances with different specific surface areas were used and the drug concentration in the suspension was varied, but the spray droplet diameter was set to 16 μm, and the nifedipine concentration in the composition was Powders of various sample compositions were prepared by setting the concentration to 10%, and a dissolution test was conducted for each sample composition in the same manner as in Example I to examine the dissolution rate (D6) after 60 minutes. The results are shown in Table 3 below, and when the specific surface area of the drug substance was 0.24 and 27 g, the nifedipine concentration in the suspension was 5x or less, and 0.8
When the concentration of nifedipine in the suspension is 8 m2/g, the concentration of nifedipine in the suspension is 20
% or less, it was found that the elution rate of the active substance could be brought to a value within an appropriate range.

In the table, (2) See Example 1, (3) Specific surface area of phezibin crystals as the drug substance, and (4) Drug substance concentration in the suspension for spraying.

KL Group' (Granules) A suspension of IOX in ethanol as a raw material was sprayed and adsorbed onto various carriers using a fluidized bed granulation dryer to form a composition and granules. In this example, the spray droplet diameter was set to 16 μm, and 1.0% of polysorbate 80 was added to the above ethanol suspension as a surfactant. Further, the raw material used had a specific surface area of 0.118 m2/g.

Dissolution rate (Dse) of the drug substance in each sample composition obtained
were investigated in the same manner as in Example 1, and the results are shown in Table 4 below, and all values were within appropriate ranges.

In the table, (1) the concentration of the drug substance in the sample composition; (2) see Example 1;
(Tablets - film tablets) Control the spray droplet diameter to 16 μm, and apply the drug substance (
A composition was prepared by spraying and adsorbing a 1.5% ethanol solution of the sample (having a specific surface area of 0.24 m2/g) onto lactose as a carrier using a fluidized bed granulation dryer.

Next, the above composition was granulated using a water/ethanol mixture as a production aid and compressed to obtain uncoated tablets.

Film tablets were obtained by treating the uncoated tablets with a coating liquid having the following formulation. In addition, the coating amount is 2-
The dose was set at 8 mg/tablet.

Coating liquid formulation: Hydroquinepropyl methylcellulose 7 parts macrogol 2 parts titanium oxide
1 part water
The dissolution rate of the drug substance in each sample tablet obtained in an appropriate amount (
The results of examining Da a ) in the same manner as in Example 1 are shown in Table 5 below, and all values were within appropriate ranges.

In the table, (2) "See Example 1, (5): Crystalline cellulose, (1;): Carboxymethyl cellulose, (7):
Surfactant (Polysorbet) 80), (8) Magnesium nistearate.

Futane 1 (tablet - uncoated tablet) The spray droplet diameter was controlled to 16 μm, and the drug substance (
A suspension of 5x ethanol (with a specific surface area of 0.24 m2/g) was formed into a composition by spray adsorption onto lactose as a carrier using a fluidized bed granulation dryer.

Next, the above composition was granulated using a water-ethanol mixture as a production aid, and the resulting composition was compressed to obtain uncoated tablets.

The dissolution rate (Dos) of the active substance in each sample tablet obtained was investigated in the same manner as in Example 1, and the results are shown in Table 6 below, and all values were within appropriate ranges.

In the L table, (2): See Example 1, (5): Crystalline cellulose, (6): Carboquinomethyl cellulose, (7): Surfactant (polysorbate 80), (8): Magnesium stearate, ( 9): Polyvinylpyrrolidone.

U properties J (Dragage-coated tablets) The uncoated tablets (tablets 4) obtained in Example 6 are then treated one after another with a coating liquid of the same formulation, and then polished with powdered Lunaubawanx (℃). Dragee-coated tablets were thereby obtained. In addition, in the coating liquid formulation below,
The dye solution was prepared by dissolving 30 g of Yellow No. 5 dye in 270 g of purified water.

Sub-coating liquid: White sugar 850 (g) Gum arabic powder 50 Purified water 450 Smoothing liquid: White sugar 850 (gl gelatin)
5 Gum arabic powder 20 Purified water 450 Precipitated calcium carbonate 1000 Coloring liquid 5 Coloring liquid: White sugar sso (g) Gelatin
5 Purified water 450 Color liquid 3 Finishing liquid: White sugar sso (g) Purified water
450 Dye solution 3g The dissolution rate (Dos) of the drug in the sugar-coated tablet obtained in this example was investigated in the same manner as in Example 1.
It was 42.8%, which was within the appropriate range (50±20%).

Futane 1 (capsule) Collect the powders At and A4 obtained in Example 2 as nifedipine in an amount equivalent to Syrg each, a total amount equivalent to 10 mg, and add an appropriate amount of crystalline cellulose and 1% amount of magnesium stearate to this. By doing this, the total amount was adjusted to 1401 g, and the mixture was filled into hard capsules (No. 4 capsules) to obtain capsules.

The dissolution rate (Dea) of the drug in this capsule was examined in the same manner as in Example 1, and was found to be 55.71, which was within the appropriate range (50±20%).

Fugoma (three-layer tablet) An amount equivalent to 5 mg of nifedipine was collected from the powder A1 obtained in Example 2, and an appropriate amount of crystalline cellulose and an amount of magnesium stearate equivalent to 1% were mixed therein to prepare the powder A1 obtained in Example 2. None, and an amount equivalent to 5 mg of nifedipine was collected from the powder (A4) obtained in Example 2, and an appropriate amount of crystalline cellulose and an amount of magnesium stearate equivalent to 1% were mixed therein to form a second layer. A three-layer tablet was obtained by laminating both layers and integrating them by tabletting.

Example 1 The dissolution rate (Das) of the drug in this three-layer tablet
The result was 52.1%, which was within the appropriate range (50±20%).

Seiroku J (Change in blood concentration) In order to investigate the effectiveness (durability of action) of the preparation obtained by the present invention, the following samples were orally administered to a volunteer panel consisting of eight healthy adult males. Blood samples were then collected over time to measure changes in drug concentration in plasma.

Test sample: Film tablet of Example 5 (according to formulation 3, containing 20 grams of nifedipine, specific surface area of drug substance crystal +
0.24m2/g).

Control sample: A film tablet prepared in exactly the same manner as the test sample, except that the active substance was not converted into a composition by spray adsorption treatment.

The results are shown in Table 7 below, and the drug concentration in the blood of the preparation manufactured by the method of the present invention reaches a high level immediately after administration, and even after 12 hours, the drug still remains effective therapeutically. Medium concentration 12 ng/ml [Kikuchi et al. "Clinical Pharmacology" Vol. +3. No 4゜page 82
3 (+982)].
Therefore, it was confirmed that it had the desired duration of action. On the other hand, the control formulation did not reach the above effective blood concentration level.

(Effects of the Invention) According to the present invention, a poorly water-soluble drug is once dissolved or suspended in a solvent, and the obtained solution or suspension is sprayed and adsorbed onto a carrier by controlling the droplet diameter of the spray liquid. The solubility of the drug can be improved by forming it into a composition, which results in sustained drug efficacy.

Therefore, when carrying out the method of the present invention, there is no restriction due to the crystal grain size or specific surface area of the drug substance, and the treatment method is extremely simple as described above. This method is industrially excellent as a formulation method for improving the solubility of water-soluble drugs and prolonging their efficacy.

Claims (6)

[Claims] (1) It is characterized by using a composition obtained by dissolving or suspending a poorly water-soluble drug in a solvent, and then spraying and adsorbing it onto a carrier while controlling the droplet size of the spray liquid.
A method for producing long-lasting formulations of poorly water-soluble drugs. (2) The poorly water-soluble drug according to claim (1), characterized in that the poorly water-soluble drug is selected from nifedipine, isosorbide nitrate, theophylline, pindolol, dihydroergotoxine mesylate, and molsidomine. Long-acting formulation method. (3) Claim (1) or (3) characterized in that the solvent is an alcohol, water, dichloromethane, acetone, or a mixture thereof, and optionally contains a surfactant.
2) The method for producing a long-lasting formulation of a poorly water-soluble drug. (4) The poorly water-soluble drug according to claim (1), (2) or (3), characterized in that when the poorly water-soluble drug is nifedipine, the droplet diameter of the spray liquid is set to 150 μm or less. Method for long-acting formulation of sex drugs. (5) When the poorly water-soluble drug is nifedipine, the nifedipine content in the composition is set to 50% or less if it contains a surfactant, and 20% or less if it does not contain a surfactant. Claims characterized in that (
1), (2), (3) or (4), the method for producing a long-lasting formulation of a poorly water-soluble drug. (6) A claim characterized in that when the poorly water-soluble drug is nifedipine, the concentration of nifedipine in the spray liquid is set to 1.7% or less as a solution and 20% or less as a suspension. A method for producing a long-lasting formulation of a poorly water-soluble drug according to (1), (2), (3), (4) or (5).